The "metastatic cascade" is a complex process involving an interplay between host defenses and tumor cell subversion of same. The proposed critical events in hematogenous metastasis are tumor cell arrest and/or attachment to endothelium or deendothelianized surfaces, extravasation from the vascular system and tumor cell growth at a secondary site. The interaction between host platelets and circulating tumor cells facilitates tumor cell metastasis by a yet undefined mechanism. We previously proposed that prostacyclin (PGI2), a natural product of the vessel wall and the most potent antithrombotic agent known, may function as an endogenous antimetastatic agent. Platelet aggregation is mediated in part by thromboxane A2 (TXA2). We have also demonstrated that platelet thromboxane synthase inhibitors TXA2SI are antimetastatic in vivo. However, they do not consistently inhibit tumor cell induced platelet aggregation (TCIPA) in vitro. To explain this discrepancy we propose the "Steal Hypothesis." Simply, during TCIPA in the presence of TXA2SI, platelet endoperoxide PGH2 can be utilized by endothelial and/or leukocyte PGI2 synthase to generate PGI2. PGI2 inhibits tumor cell-platelet adhesion to endothelium. In vitro platelet, tumor cell, and endothelial cell or leukocyte coincubation studies with and without specific arachidonic acid cascade inhibitors will test this hypothesis for TCIPA and TC adhesion to endothelium. Metabolites generated during coincubation studies will be measured by HPLC and/or RIA. Five TXA2SI representing two structural classes will be tested in vitro and in vivo. The "Steal Hypothesis" will also be tested in vivo using specific inhibitors (12-HPETE) of PGI2 synthesis. In addition we will explore the mechanism by which tumor cells facilitate metastasis. We propose that one or a combination of platelet derived products (i.e., serotonin, TXA2, 12-HETE or FVIII:von Willebrand) enhance tumor cell adhesion. The proposed research should yield important, relevant data concerning: 1) mechanism of action of TXA2SI, 2) mechanism of platelet facilitated metastasis, and 3) a new class of antitumor/antimetastatic agents with direct applicability to human cancer.